Ketoprofen (Trade Name Orudis) is a known anti-inflammatory agent and one of the substituted propionic acids that inhibits prostaglandin-endoperoxide synthase. Propionic acid derivates are used in the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and acute gouty arthritis. They are useful as analgesics, for acute tendinitis and bursitis, and for primary dysmenorrhea. In addition, they are very effective analgesics to relieve postpartum pain, and following oral, ophthalmic, or other types of surgery.
Clinical studies indicate that the propionic acid derivatives are comparable to aspirin for the control of the signs and symptoms or rheumatoid arthritis—there is a reduction in joint swelling, pain, and duration of morning stiffness. By objective measurements, strength, mobility, and stamina are improved. In general, the intensity of untoward effects is less than that associated with the ingestion of indomethacin or high doses of aspirin. However, aspirin is less expensive than most of the proprionic derivatives for those who can tolerate it.
Adverse effects include gastrointestinal complaints including nausea, vomiting, epigastric pain, reactivation of peptic ulcer, and other disturbances are common to all members of this group. CNS-related effects, such as dizziness, drowsiness, headache, and fatigue, also may occur. Drug interactions are not many, but since these drugs are very highly protein-bound, competition for binding sites could present a problem with oral anticoagulants or other highly protein-bound drugs. Toxicity is related primarily to the gastrointestinal tract, where ulceration and bleeding can be a problem.
Other members of the propionic acid derivative family include ibuprofen, naproxen, flurbiprofen, fenoprofen, and oxaprozin. The pharmacodynamics properties of the propionic acid derivatives do not differ significantly. All are effective cyclooxygenase inhibitors, although there is considerable variation in their potency. All of these agents alter platelet function and prolong bleeding time, and it should be assumed that any patient who is intolerant of aspirin also may suffer a severe reaction after administration of one of these drugs. Some of the propionic acid derivatives have prominent inhibitory effects on leukocyte function; naproxen is particularly potent in this regard. All are effective antiinflammatory agents in various experimental animal models of inflammation. All have useful antiinflammatory, analgesic, and antipyretic activities in human beings. Although all of these compounds can cause gastrointestinal side effects in patients, these are usually less severe than with aspirin.
Although it is a cyclooxygenase inhibitor, ketoprofen is believed to stabilize lysosomal membranes and may antagonize the actions of bradykinin. Ketoprofen has the general formula 
In humans, ketoprofen is rapidly absorbed after oral administration and maximal concentrations in plasma are achieved within 1 to 2 hours; food reduces the rate but not the extent of absorption. Ketoprofen, however, is distributed unevenly in body water. The drug is extensively bound to plasma proteins (99%) and it has a half-life in plasma of about 2 hours; slightly longer half-lives are observed in elderly subjects. The plasma half-life may vary between 1 and 35 hours; the causes of this variability are unknown. Ketoprofen is conjugated with glucuronic acid in the liver and the conjugate is excreted in the urine. Patients with impaired renal function eliminate the drug more slowly.
The claimed invention consists of forming a stable solution of ketoprofen in water for use in mass medicating animals and the addition of a flavoring agent to increase palatability. Current products on the market are given by injection and create significant problems if used for mass medication of farm animals (e.g., swine, cattle, horses, sheep, chickens, and goats) or for ongoing medication of small animals (e.g., dogs and cats). For example, injecting ketoprofen is time consuming and costly, especially with large numbers of animals involved. It is also potentially hazardous to the animal because a needle can break off in the animal and/or create an infective injection site. Feed even a farmyard animal, let alone a wildlife species, with tablets is minimally a taxing chore.
The claimed invention, a stable liquid form of ketoprofen, reduces concerns about the injection site, reduces the stress on the animal, allows for continuous medication over time at lower doses, and induces a steady state of drug in the animal's system. These advantages of the present invention reduce the potential for adverse affects on the animal. Such advantages also decreases the clearance time from removal of the drug to total body elimination due to the lack of the injection site.
The ability to administer ketoprofen in a non-invasive manner allows for the treatment of large groups of animals and for easier long-term treatment of individual animals with chronic disease. This formulation should prove beneficial in any condition where acute or chronic inflammation is involved where a desire to not give injections or pastes or pills is beneficial.
Although a number of references teach the use of ketoprofen, the ketoprofen compound itself is used with suitable organic and inorganic bases or oily solutions.
U.S. Pat. No. 6,069,172 (Bertini) describes a new use of the enantiomer (R)-ketoprofen and its salts with suitable organic and inorganic bases in the therapy of neutrophil-dependent diseases and phlogistic processes in a patient, and pharmaceutical preparations containing such compounds and useful for oral, parenteral or topical administration.
U.S. Pat. No. 5,665,384 (Courteille) describes stable, pharmaceutical ketoprofen salts for oral admininstration in oily solutions to avoid direct contact of acid forms of ketoprofen with the gastric or duodenal mucus membranes. Sodium, arginine, lysine and/or N-methylglucamine salts of ketoprofen are disclosed in solutions of polyoxyethyenatide vegetable oil, castor oil, esters of fatty acids and/or polyols. These oily solutions of ketoprofen may be administered orally in capsule form.
Still other references describe the anlagesic and antipyretic activity of related agents or in some cases ketoprofen, without providing a stable, liquid form of administration.
Scand. J. Rheumatology, Suppl. 14: 33-44 (1976) describes the main pharmacological properties of ketoprofen, especially its anti-inflammatory, analgesic and antipyretic activity. Ketoprofen possesses the typical pharmacological properties of non-steroidal anti-inflammatory agents, i.e., anti-inflammatory, analgesic and antipyretic activity, as well as antibradykinin activity and ability to inhibit prostaglandin synthesis.
Bull. Soc.Vet.Prat.de France, 7/90, T. 74, No.7, p. 377 describes the use of ketoprophene as analgesic therapy in the treatment of equine colic (administered intravenously). A dosage of 2 mg per kg or 2 mL of 10% Ketoprofen solution per 100 kg was used.
Equine Vet. J. 19(1), 60-66 (1987) “Use of a novel non-steroidal anti-inflammatory drug in the horse” describes the use of a novel oral phenylpyrazoline anti-inflammatory agent (BW540C). An acute inflammatory reaction was generated by injecting carrageenin solution into subcutaneously-implanted tissue-cages lined with fibrovascular granulation tissue. BW540C inhibited platelet cyclo-oxygenase for 24 h but the reductions in exudates elcosanoid concentrations were less pronounced.
There is a need for stable liquid forms of ketoprofen that can be orally administered (i.e., ingested) via an animal's drinking water without rejection by the animal because of the bad taste imparted by the liquid ketoprofen. Such a palatable form of ketoprofen allows large scale dosage-controlled treatment of animals with the antibiotic.